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A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis

Scally, S., Petersen, J., Law, S., Dudek, N., Nel, H., Loh, K., Wijeyewickrema, L., Eckle, S., van Heemst, J., Pike, R., McCluskey, J., Toes, R., La Gruta, N., Purcell, A., Reid, H., Thomas, R. and Rossjohn, Jamie 2013. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. Journal of Experimental Medicine 210 (12) , pp. 2569-2582. 10.1084/jem.20131241

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Abstract

Rheumatoid arthritis (RA) is strongly associated with the human leukocyte antigen (HLA)- DRB1 locus that possesses the shared susceptibility epitope (SE) and the citrullination of self-antigens. We show how citrullinated aggrecan and vimentin epitopes bind to HLADRB1* 04:01/04. Citrulline was accommodated within the electropositive P4 pocket of HLA-DRB1*04:01/04, whereas the electronegative P4 pocket of the RA-resistant HLADRB1* 04:02 allomorph interacted with arginine or citrulline-containing epitopes. Peptide elution studies revealed P4 arginine-containing peptides from HLA-DRB1*04:02, but not from HLA-DRB1*04:01/04. Citrullination altered protease susceptibility of vimentin, thereby generating self-epitopes that are presented to T cells in HLA-DRB1*04:01+ individuals. Using HLA-II tetramers, we observed citrullinated vimentin- and aggrecan-specific CD4+ T cells in the peripheral blood of HLA-DRB1*04:01+ RA-affected and healthy individuals. In RA patients, autoreactive T cell numbers correlated with disease activity and were deficient in regulatory T cells relative to healthy individuals. These findings reshape our understanding of the association between citrullination, the HLA-DRB1 locus, and T cell autoreactivity in RA.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
R Medicine > RZ Other systems of medicine
Uncontrolled Keywords: Aggrecans; Amino Acid Sequence; Animals; Antigen Presentation; Arthritis, Rheumatoid; Autoantigens; CD4-Positive T-Lymphocytes; Citrulline; Epitopes; Genetic Association Studies; HLA-DR beta-Chains; HLA-DR4 Antigen; HLA-DRB1 Chains; Humans; Mice; Mice, Transgenic; Models, Molecular; Molecular Sequence Data; Polymorphism, Genetic; Vimentin
Publisher: Rockefeller University Press
ISSN: 0022-1007
Last Modified: 04 Jun 2017 08:20
URI: http://orca-mwe.cf.ac.uk/id/eprint/76108

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